Dibenzoxazepine and dibenzothiazepine alkanonitriles

ABSTRACT

Disclosed herein are dibenzoxazepine and dibenzothiazepine derivatives which are substituted in the 5-position with a carboxyalkylene group. These compounds have been found to stimulate the central nervous system and to produce analgesia.

United States Patent Yale et al.

DIBENZOXAZEPINE AND DIBENZOTHIAZEPINE ALKANONITRILES Inventors: HarryLouis Yale; Remesh Petigara,

both of New Brunswick, NJ.

Assignee: I E, R. Squibb & Sons, Inc., Princeton, NJ. I

Filed: Sept. 15, 1971 App]. No.: 180,905

Related U.S. Auplication Data Division of Ser. No. 13,767, Feb. 24,1970, Pat. No. 3,702,852. A

US. Cl. 260/327 B, 260/333, 424/275,

- Y 424/278 Int. Cl. A61k-27/00, C07d 93/42, C07d 87/54 Field of Search"260/327 B, 333

[4 1 June 26, 1973 Primary Examiner-Henry R. Jiles AssistantExaminer-Cecilia M. S. Jaisle Attorney-Lawrence S. Levinson et al.

[57] ABSTRACT Disclosed herein are' dibenzoxazepine anddibenzothiazepine derivatives which are substituted in the 5- positionwith a-carboxyalkylene group. These compounds have been found tostimulate the central nervous system and to produce analgesia.

" s Claims,'No Drawings DIBENZOXAZEPINE AND DIBENZOTHIAZEPINEALKANONITRILES This is a divisional application of Ser. No. 13,767, nowUS. Pat. No. 3,702,852.

SUMMARY OF INVENTION This invention relates to dibenzoxazepinederivatives having the formula I:

A-COOH wherein A is lower alkylene (e.g., from one to six carbons); Xand X are halogen (e.g., chloro-, bromo-, iodo and fluoro-) orhalo-alkyl, e.g., CF Y is O or S; mandnare0,1or2.

The terms lower alkylene and lower alkyl when utilized in this inventionrefer to straight or branched chain hydrocarbon groups of from about oneto six carbon atoms, such as methylene, ethylene, propylene,isopropylene, butylene, isobutylene, amylene, and the like. Halogenrefers to fiuoro, chloro-, bromoor iodo.

It has been widely recognized that very special chemical structuralrequirements are essential for a substance to pass the mysteriousblood-brain barrier and to enter the central nervous system. Many of theataractic agents in current use, for example, possess strongly basicside chains and it is generally assumed that this is an essentialstructural requirement for entrance into the brain. It is thereforesomewhat surprising to find that the compounds of this invention,possessing a carboxylic acid group on the side chain, readily pass theblood-brain barrier to produce centra nervous system stimulation andanalgesia.

The compounds of this invention can be administered perorally or by anyother noteable means, e.g., tablets, in amounts of from about mg./kg. ofbody weight to about 35 mg./kg. of body weight and preferably can beutilized in a manner similar to imipramine.

The compounds of this invention are prepared by several methods. Thus,reacting compounds having the formula II:

with a nitrile of formula I (e.g., acrylonitrile, 2-

methylacrylonitrile, 2-isopr0pylacylonitrile, 2- pentylacrylonitrile,and so forth):

wherein R is H or a lower alkyl group (e.g.,straight or,

compounds of formula lV:

wherein n, m, X, X, Y and R are as defined herein.

This reaction is carried out by employing an excess of thenitrileCl-hzCI-IRON as the solvent. The temperature utilized in the reactioncan be varied from about 0 to about C. with the preferred range beingbetween about 0 and about 75 C. This reaction proceeds expeditiouslywhen a small amount (up to about I percent) of a strong base like sodiumhydroxide, sodium methoxide, potassium t-butoxide, or benzyltrimethylammonium hydroxide (Triton B) is used as the catalyst.

Compounds with the nitrile structure (IV) are converted to carboxylicacid of formula I by heating at reflux temperatures with sufficientaqueous or alcoholic alkali metal hydroxide, e.g., sodium hydroxide orpotassium hydroxide in methanol or ethanol.

However, the preferred procedure for preparting compounds of formula Iis to treat the compounds of structure IV with alcoholic hydrogenhalide, such as hydrogen chloride in methanol, ethanol, and so forth, atroom temperature whereby esters of the structure V are formed. Bysaponifying Compound V with an alkali metal hydroxide, e.g., sodiumhydroxide, lithium hydroxide, and so forth, the desired carboxylic acidsof structure I can be recovered:

- )n I )m o omcHo I t OR v wherein m, n, R, X, X, and Y are as definedabove and R is lower alkyl.

Alternatively, a general procedure for preparing the compounds ofstructure I which may be utilized is to react the compounds havingformula II with a haloalkylenecyanide of the general structure Vl whereX is halogen, e.g., chloro, iodo bromo; and A is. as defined herein.This yields a nitrile of formula IV:

X" -A-CN Examples of haloalkylenecyanide reagents that may be utilizedare 3-chloropropionitrile, 3- bromobutyronitrile, and so forth. Thereaction may be carried out in an alcohol, such as ethanol, propanol,and so forth, as the solvent, in the presence of at least one molarequivalent of anhydrous potassium carbonate, or in an aromatic solventlike benzene, toluene, or xylene, using at least one molar equivalent ofalkali metal hydroxide, e.g., sodium hydride, lithium hydride, and soforth, or alkali metal amine, e.g., sodium amide or in an aliphaticketone like acetone or ethyl methyl ketone using at least one molarequivalent of powdered alkali metal hydroxide, e.g., sodium hydroxide orlithium hydroxide. The desired temperature in these reactions is between60 and C. The compounds of formula IV prepared by these reactions may bethereafter treated as indicated above to yield compounds of formula I.

Examples of dibenzoxazepines and dibenzthiazepines that can be utilizedin the practice of this invention are: 7-chloro-5,ll-dihydrodibenz[b,e][ l.4]oxazepine; 7,8-

3 dichloro-5,l l-dihydrodibenz[b,e][ 1,4]xazepine; 3- chloro-5,ll-dihydrodibenz[b,e][1,4]oxazepine; 3-

EXAMPLE I 7-Chloro-5,l l-dihydrodibenz[b,e][ 1,4]oxazepine-- propionicacid a. 7-Chloro-5,l 1-dihydrodibenz[b,e][ 1,4]oxazepine-5-propionitrile.

A suspension of 17.4 g. of 7-chloro-5,1ldihydrodibenz[b,e][1,4]oxazepinein 35 ml. of acrylonitrile is cooled to 05. To this is added withefficient stirring and cooling 0.2 ml. of Triton B. The suspensionbecomes homogeneous and a red solution results with the rise oftemperature to The reaction mixture is allowed to come to roomtemperature and then refluxed for 1 hour with stirring. The excess ofacrylonitrile is removed by known means, water is added, and the solidis filtered. The solid is dried, powdered, and extracted with five 400ml. portions of diethyl ether. The diethyl ether extracts are dried andconcentrated to a volume of 250 ml. The white crystalline compound isfiltered. The filtrate is again concentrated and the resulting solid isfiltered. The yield of the combined desired products is 21.5 g., m.p.about l3ll32.

b. 7-Chloro-5,l l-dihydrodibenz[b,e][1,4]oxazepine- 5-propionic acid,Methyl Ester.

The product from (a), 7-chloro-5,l l-' dihydrodibenz[b,e]-[ l,4]oxazepine-S-propionitrile, 71.10 g., is dissolved in 1200 ml. of drydioxane and to this 800 ml. of 30% methanolic hydrogen chloride isadded. The solution is stirred for 72 hours, 30 ml. of H 0 is added, themixture is stirred for 0.5 hour, concentrated in vacuo to 400 ml.,filtered, and the filtrate concentrated to dryness in vacuo. Theresidue'solidifies on keeping to yield the produce 67.5 g., m.p. about70-72.

c. 7-Chloro-5,l l-dihydridibenz[b,e][1,4]oxazepine- S-propionic acid.

The product from (b), 7-chloro-5,1ldihydrodibenz[b,e][ l,4]oxazepine-5-propionic acid, methyl ester, 25.4 g. is dissolved in2,200 ml. of MeOH and to this 5.6 g. of KOl-l dissolved in 300 ml. of H0 is added. The solution is refluxed for 4 hours, and then isconcentrated in vacuo. The residue is taken up in 600 ml. of H 0, thesolution is cooled, and then acidified with 2% aqueous HCl. The solid isfiltered and dissolved in 600 ml. of C H This solution is treated withDarco and then extracted with 600 ml. of 2% aqueous NaOH solution. Theextracts are treated with Darco and Hyflo, filtered andthe filtrate isacidified with 2% aqueous HCl. The solid is filtered and recrystallizedfrom C l-1 The yield is 23.0 g. m.p. about l55.0-l56.5.

EXAMPLE 2 5,1 l-Dihydro-7-(trifluoromethyl)dibenz[b,e][ l,4]-oxazepine-S-propionic acid o 4 A a. 5,1 l-Dihydro-7-(trifluoromethyl)dibenz[b,e][ l,4]-o azepine-S- propionitrile.

To 50.0 g. of 5,1 l-dihydro-7-(trifluoromethyl)dibenz-[b,e][1,4]oxazepine in 60 ml. of redistilledacrylonitrile is added in 5 minutes 0.80 ml. of Triton B. Subsequently,the mixture is heated for one hour under reflux and the product isolatedby extraction with benzene to give 5,1 l-dihydro-7-(trifluoromethyl)dibenz[b,e][ l ,4]oxazepine-5- propionitrile, m.p.about 16ll63.

(trifluoromethyl)dibenz[b,e][ l ,4]-oxazepine-5- propionic acid, MethylEster.

7-Trifluoromethyl-5 ,1 l-dihydrodibenz[b,e][ l ,4]-oxazepine-S-pripionitrile, 15.0 g., is dissolved in 240 ml. of drydioxane and to this 140 ml. of 30% methanolic hydrogen chloride isadded. The solution is stirred for 36 hours, 6 ml. of H 0 is added,stirred 0.5 hour, and then concentrated in vacuo to ml. The solid isfiltered, and the filtrate is concentrated to dryness in vacuo. Theresidual liquid is taken up in 200 ml. of diethyl ether, treated withDarco and Hyflo, the diethyl ether solution is concentrated and theresidue distilled in vacuo to give 5,1 l-dihydro-7-(trifluoromethyl)-dibenz[b,e][1,4]oxazepine-5-propionic acid, methyl ester, b.p. aboutl66-l68 (0.08 mm.), m.p. about 70.07l.5.

c. 5,1 l-Dihydro-7- (trifluoromethyl)dibenz[b,e][ 1,4]-oxazepine-5-propionic acid.

7-Trifluoromethyl-5 ,l ldihydrodibenz[b,e][ l ,4]oxazepine-5-propionicacid, methyl ester, 3.15 g., is dissolved in 315 ml. of methanol and tothis 0.5 g. of potassium hydroxide dissolved in 25 ml. of water isadded. The mixture is refluxed for 2.5 hours and then concentrated invacuo. The residue is taken up in 250 ml. of water and this solution isacidified with 2% aqueous HCl to give 5,11-dihydr0-7-(trifluoromethyl)-dibenz[b,e][ 1,4]oxazepine-5- propionic acid, m.p.about 9496.

EXAMPLE 3 5,1 1-Dihydro-7-(trifluoromethyl)dibenz[b,e][1,4]-oxazepine-S-butyric acid a. a, a,a-Trifluoro-6'-hydroxy-m-formotoluidide.

Hydrogenation of 66.0 g. of a, a, a-trifluoroZ-nitrop-cresol, 6.0 g. 5%Pd-C, and ml. of absolute ethanol at 3.5 kg./cm is complete in 1 hour.To the filtered ethanol solution is added 94 ml. of 98-100% HCOJ-l andthe ethanol distilled under N, by means of a steam bath until the stillhead temperature reaches 82. The residual liquid is heated 1 hour underreflux, cooled somewhat, and poured with stirring on 270 g. of ice togive 55.3 g. of a, a, a-trifluoro-6'-hydroxy-mformotoluidide, m.p. aboutl74l76.

b. 6-[o-Bromobenzyl)oxy]-a, a, a-trifluoro-mformotoluide. v

To 256.0 g. of the product from a), 324.0 g. ofo bromobenzyl bromide,and 2,600 ml. of absolute ethanol, is added in one hour, 69.8 g. ofNaOMe in 750 ml. of absolute ethanol. The solution is stirred at roomtemperature for 5 hours and then is poured into 12 l. of water, agitatedthoroughly, the solid is filtered, and airdried to give 551.0 g. ofproduct m.p. about 1S9-l60.

c. 5 ,1 1-Dihydro-7-( trifluoromethyldibenz[b,e][1,41-oxazepine.

5,1 l-Dihydro-7- To 1,960 ml. of N,N-dimethylformamide 164.0 g. of K COand 14.0 g. of copper bronze, under reflux, is added in two hours asolution of 233.0 g. of the product from (b) in 1960 ml. ofN,N-dimethylformamide. During the addition, after one hour, anadditional 86.0 g. of K CO is added. Subsequently, stirring and heatingunder reflux are continued for 1.5 hours, the mixture is filtered hot,and the filtrate concentrated in vacuo to dryness. The residueconsisting of 5,1 l-dihydro-7-(trifluoromethyl)dibenz[b,e][1,4]oxazepine-- carboxaldehyde is dissolvedin 1,560 ml. of 95% ethanol, 312 m1. of 25% aqueous sodium hydroxide;the mixture heated under reflux for 1 hour and again concentrated todryness in vacuo. The residual solid is washed thoroughly with water,filtered, and air-dried to give 141.0 g.5,1l-dihydro-7-(trifluoromethyl)di benz[b,e][ l,4]-oxazepine m.p. about126-127.

d. 5 ,1 1-Dihydro-7- (trifluoromethyl)dibenz[,b,e][ 1 ,4]-oxazepine-5-butyronitrile.

To a suspension of 25.5 g. of the product from (c), 250 ml. of ethylmethyl ketone, 0.5 g. of copperbronze, and 16.0 g. of powdered NaOl-l isadded dropwise in 0.5 hour 29.6 g. of 4-bromobutyronitrile. The mixtureis stirred and refluxed for hours, cooled, and filtered. The filtrate isconcentrated in vacuo to remove all volatile material, and the residueis dissolved in 25 ml. of methanol to give 5,1l-dihydro-7-(trifluoromethyl)-dibenz[b,e][ 1,4]oxazepine-5- butyronitrile.

e. 5,1 1-Dihydro-7- (trifluoromethyl)dibenz[b,e][1,4]oxazepine-5-butyricacid, Methyl Ester.

The product from (b), 80.5 g., is substituted for the 7-chloro-5,l1-dihydrodibenz[b,e][ 1,4]oxazepine-5- propionitrile in Example 1 (b),to give 5,1l-dihydro-7- (trifluoromethyl)dibenz[b,e][ l,4]-oxazepine-5-butyric acid, methyl ester.

f. 5,1 l-Dihydro-7- (trifluoromethyl)dibenz[b,e][1,4]oxazepine-5-butyric acid.

The product from (e), 27.3 g., substituted for the 7- chloro-S ,1l-dihydrodibenz[b,e][ 1,4]oxazepine-5- propionic acid, methyl ester inExample 1 (c), gives 5,- 1 1-dihydro-7-(trifluoromethy1-dibenz[b,e][1,4]oxazepine-S-butyric acid.

EXAMPLE 4 3,7-Dichloro-5 ,1 l-dihydrodibenz[b,e][1,4]oxazepine 5-aceticacid a. 2-Bromo-p-chlorotoluene and 2,5-dibromo-4- chlorotoluene.

To 508.0 g. of p-chlorotoluene and 50 g. of powdered iron powder at25-30 is added 880.0 g. of bromine in 3.5 hours, the whole filtered, andthe filtrate (n,, 1.58- 50) distilled to give 456.3 g. of2-bromo-pchlorotoluene, b.p. about 105-1 10 (3mm), n 1.5731. The residuefrom the 2-bromo-p-chlorotoluene distils at 180-1 85 (0.1 mm) andcrystallizes spontaneously. Recrystallization from hexane gives 247.5 g.of 2,5-dibromo-4-chlorotoluene, m.p. about 9495; its nmr spectrum showedtwo one proton singlets at r 2.38 and 2.51, attributable, respectively,to the protons at C and C,,, as well as the 3-proton singlet at 7.64 dueto the methyl protons.

b. 2-Bromo-4-chlorobenzyl Bromide To 435 g. of Z-bromo-p-chlorotolueneand 3.0 g. of benzoyl peroxide, heated in an oil bath at 120 andirradiated by a UV lamp, is added 360 g. of Br, in 4.5 hours, and themixture 'pruged with N, to give 2-bromo- 4-chlorobenzyl bromide, N1.6215.

c. 3,7-Dich1oro-5,1 1-dihydrodibenz[b,e][ l ,4]oxazepine.

The subsequent steps in this synthesis followed the reported procedure[H. L. Yale and F. Sowinski, J. MED. CHEM. l, 609 (1964)] to give first2-bromo-4- chlorobenzyl-4-ch1oro-2-nitrophenyl ether, m.p. about l-167,then the aniline hydrochloride, m.p. about 204205, and the formanilide,m.p. about 15 515 6. A mixture of 23.0 g. of the formanilide, 51.0 g. ofpotassium carbonate, 1.58 g. of copper-bronze, and 450 ml. ofdiethylbenzene is stirred vigorously and heated under reflux for threehours, filtered, and the filtrate is concentrated to dryness in vacuo togive 13.1 g. of 3,7- dichloro-5,1 1-dihydrodibenz-[b,e][1,4]oxazepine-5- carboxaldehyde. Then 13.1 g. of this product, ethanol,and 10 ml. of 25% aqueous sodium hydroxide are heated under reflux for0.5 hour and concentrated in vacuo to give 9.8 g. of 3,7-dich1oro-5,ll-dihydridibenz- [b,e][1,4]oxazepines m.p. about l58-l60.

d. 3,7-Dich1oro-5,l l-dihydrodibenz[b,e][1,4]oxazepine-S-acetic acid.-

By substituting 15.1 g. of chloroacetonitrile for the 4-bromobutyronitrile in Example 3 d), there is obtained 3 ,7-dichloro-5} l1-dihydrodibenz[b,e][ 1,4 ]oxazepine- S-acetonitrile. When equimolaramounts of the 5- acetonitrile derivative is then substituted for the 5-butyronitrile in Example 3(e), there is obtained 3,7- dichloro-S ,ll-dihydrodibenz[b,e][ l,4]oxazepine-5- acetic acid, methyl ester, and anequimolar amount of the S-acetic acid, methyl ester substituted for the5- butyric acid, methyl ester in Example 3 e) gives 3,7- dichloro-5 ,1l-dihydrodibenz[b,e 1,4]oxazepine-5- acetic acid.

EXAMPLE 5 EXAMPLE 6 3-Chloro-5,1 l-dihydrodibenz[ b,e][ 1,4]oxazepine-5-propionic acid a. 3-Chloro-5 ,1 l-dihydrodibenz[b,e][ l ,4]oxazepine-5-propionitri1e.

A suspension of 24.4 g. dihydrodibenz[b,e]-[1,4]oxazepine in 55 ml. ofacrylonitrile is cooled to 0-5. To this is added with efficientstirring, and cooling, 0.3 ml. of Triton B, pausing after each drop ofaddition. The temperature rises slowly 5 ,11-Dihydrodibenz[b,e][1,4]oxazepine-5-.

of 3-chloro-5,l l- I from 3 to 14 and then rapidly to 45 within minuteswith the formation of red colored clear solution. The mixture is cooledto 5l0, stirred for 5 minutes, allowed to come to room temperature andthen slowly heated to reflux temperature. After 1 hour heating underreflux, the excess of acrylonitrile is removed in vacuo. The residue isextracted with 3-350 ml. portions of diethyl ether, the combined diethylether extracts are treated with 3.0 g. of Darco and 1.0 g. of Hyflo,filtered, the filtrate is dried, and concentrated to give 31.6 g. of3-chloro-5 ,1 l-dihydrodibenz[b,e][ 1,4]oxazepine- S-propionitrile, b.p.about 200-210 (0.2 min.).

b. 3-Chloro-5,1 l-dihydrodibenz[b,e][ 1,4]oxazepine- 5-propionic acid,Methyl Ester.

By substituting 71.1 g. of the product from (a) for the 7-chloro-5 ,ll-dihydrodibenz[b,e][ 1,4]oxazepine-5- propionitrile in Example 1 b),there is obtained 3- chloro-S ,l l-dihydrodibenz[b,e][ 1,4]oxazepine-5-propionic acid, methyl ester.

c. 3-Chloro-5 ,l l-dihydrodibenz[b,e][ 1,4 ]oxazepine- S-propionic acidThe replacement in Example 1 (c) of the 7-chloro- 5 ,1 l-dihydrodibenz[b,e][ 1 ,4]oxazepine-5-propionic acid, methyl ester with 25.4 of theproduct from (b) and then following the other details of that procedure,there is obtained 3-chloro-5,l l-dihydrodibenz- [b,e][1,4]oxazepine-5-propionic acid.

azepine-isobutyric Acid a. 2,5-Dibromo-4-chlorobenzyl Bromide Bysubstituting 650 g. of 2,5-dibromo-4- chlorotoluene (prepared in Example4) for the 453 g. of 2-bromo-4-chlorotoluene in Example 4(b), there isobtained 2,5-dibromo-A-chlorobenzyl bromide.

b. 2-Bromo-3-chloro-5 ,1 l-dihydrodibenz[b,e][ l 4]oxazepine.

The subsequent steps in this synthesis followed the reported procedures(See Example 4) and gave in turno-[2,5-dibromo-4-chlorobenzyloxyformanilide, m.p. about l203 and2-bromo-3-chloro-5,l ldihydrodibenz[b,e][1,4]oxazepine, m.p. about187-l89.

c. 2-Bromo-3-chloro-5,l ldihydrodibenz[b,e][ l,4]oxazepine-S-isobutyricacid.

Followig the procedure of Example 2 (a) but substituting 59.5 g. of2-bromo-3-chloro-5,l ldihydrodibenz[b,e][1,4]oxazepine for the 5,11-dihydro-7-(trifluoromethyl)dibenz[b,e][ 1,4]oxazepine in that exampleand employing 65 ml. of methacrylonitrile in place of acrylonitrile,there is obtained 2- bromo-3-chloro-5,ll-dihydrodibenz[b,e][1,4]oxazepine-S-isobutyronitrile. When theisobutyronitrile in equimolar quantity is substituted in the procedureof Example 2 (b), thereis obtained 2-bromo-3-chloro- 5,1l-dihydrodibenz[b,e][ l ,4]oxazepine-5-isobutyric acid, methyl ester,and when the latter, in equimolar quantity is substituted in theprocedure of Example 2 (c), there is obtained the desired2-bromo-3-chloro- 5 ,1 l-dihydrodibenz[ b,e][ l,4]-oxazepine-5-isobutyric acid.

EXAMPLE 8 7-Chloro-5 ,l l-dihydrodibenzo[b,e l ,4] thiazepine-5-(a-pentyl)propionic Following the procedure of Example 2 but utilizing7-chloro-5,l l-dihydrodibenzo[b- ,e][l,4]thiazepine in lieu of7-chloro-5,l ldihydrodiben'zo[b,e][1,4]oxazepine anda-pentylacrylonitrile in lieu of acrylonitrile the product formed in7-chloro-5 ,l l-dihydrodibenzo-[b,e][ 1,4]-thiazepine-5-(a-pentyl)propionic acid. The procedure of Example 2(b) isthen .followed to give 27.3 g. of 7- chloro-S ,1 l-dihydrodibenzol b,el,4]thiazepine-5-( apentyl)propionic acid, methyl ester.

The latter product, 26.9 g., is dissolved in 325 ml. of MeOH and to this4.9 g. of KOH dissolved in ml. of 11,0 is added. The mixture is heatedunder reflux for 2.5 hours, concentrated in vacuo and the residue takenin 250 ml. of 11,0. The solution is treated with Darco and Hyflo,filtered, and acidified with hydrochloric acid to give 22.7 g. of7-chloro-5,l l-dihydrodibenzob,e][ l,4]thiazepine-5-(a-pentyUpropionicacid.

EXAMPLE 9 3-Chloro-5,l l-dihydrodibenz[b,e][ 1 ,4]oxazepine-5- propionicacid a. 2-o-Bromo-p-chlorobenzyloxy nitrophenyl Ether To 192.0 g. of2-bromo-4-chlorobenzyl bromide and 105.0 g. of nitrophen'ol is addeddropwise a solution of 60 ml. of 50% aqueous sodium hydroxide in 750 ml.of 95% ethanol. The mixture is then refluxed for 2 hours, cooled, thesolid filtered, washed well with water, and

2 dried to give 152.0 g. of product, mp about -122.

b. o-(2-Bromo-4-chlorobenzyloxy)aniline Hydrochloride To 2,200 ml. of2-propanol, 120 ml. of H 0, and 138.0 g. of the product from (a), heatedto 50, is added at 10 minute intervals, 5 portions, each portionconsisting of 51.2 g. of iron powder and 5.2 ml. of concentratedhydrochloric acid. Subsequently, the mixture is refluxed 1 hour,filtered, the filtrate diluted with 72 ml. of concentrated hydrochloricacid, and cooled. The precipitated solid melts at 2l0-2l2; concentrationof the filtrate from this solid to about 1 l. and cooling givesadditional solid, mp about 209-21 1.

c. 2'-(2-Bromo-4-chlorobenzyloxy)formanilide A. The above product from(b), 84.0 g., 34.0 g. of sodium formate, and 460.0 g. of 98-100% formicacid are heated under reflux for 3 hours, cooled, and poured on 1 kg. ofice. The solid is extractedinto 2 l. of chloroform, the chloroformsolution is dried, filtered, and the filtrate concentrated to give 59.8g. of product, mp about l40-l44.

d. 3-Chloro-5,1 l-dihydrodibenz[b,e][ 1,4]oxazepine Copper bronze, 0.70g. and 4.36 g. of K,CO;, in 200 ml. of N,N-dimethylformamide is broughtto reflux and with stirring, a solution of 10.8 g. of 2'-(2-bromo-4-chlorobenzyloxy)formanilide in 200 ml. of N,N-dimethylformamide is addedover aperiod of 2 hours. After "me first ham 61" the addition, -4.36 g.o t KICO, is added. After the addition of the formanilide is completed,the suspension is stirred at reflux for 1.5 hours and then filtered hot.The solvent is removed is rerrged from the fi ltrate in @9939 12.3 gI' 71503? v 16 ml. 25% aqueous sodium hydroxide solution. The

solid; this is dissolved in 80 rnl.

solution is refluxed 1 hour, the EtOl-l is removed, the residue isslurried with 50 ml. of H 0 filtered, and washed with water. The crudeproduct is dried to give 6.98 g. of 3-chloro-5,l l-dihydrodibenz[b,e]

[l ,4]oxazepine, mp about 1 l31 15.

e. Following the procedure of Example 1, but utilizing 3-chloro-5 ,ll-dihydrodibenz {b,e][ l ,4 ]oxazepine 9 in lieu-of 7-chloro-5,1l-dihydrodibenz[b,e][ l,4]oxazepine the desired product is recovered.

EXAMPLE 10 Following the procedures of Example 1 but utilizing compoundsof the formula illustrated in Column A in lieu of 7-chloro-5,ll-dihydrodibenz[b,e][ 1,4]oxazepine and compounds of the formulaillustrated in C01- umn B, the products recovered are as indicated inC01- umn C:

wherein A is lower alkylene, X and X are selected from the groupconsisting of halogen and trifluoromethyl, Y is selected from the groupconsisting of oxygen and sulfur and mud n are selected from the group 5consisting of O, 1 and 2.

2. A compound having the formula:

1 lower alkylenu-CN Utilizing the reagent-illustrated in Column A inlieu of 5 ,1 l-dihydro-7-(trifluoromethyl)dibenz[b,e][ l 4]oxazepine ofExample 3 and the reagent in Column B in lieu-of 4-bromobutyronitrile ofExample 3 and following the procedures set forth therein the productsrecovered are as illustrated in Column C:

whe re i n X, X; m and n are as d e fined in claim 3. A compound ofclaim 1 having the formula:

( h (X)m lower alkyleneCN C] s Cl-CIIzCHCN s I I c m-c1n Cl \N/ 0m 01 \NCH2CI{-COOI'I Example 12 CHCHa 0- ICHECHZCN o- 1 1 CHZCHZCOOH Example 13s BrCIhCHCN 0 \N/ ---1 CH3 \llq/ I cmmho00u 011, Example 14 CIIJ What isclaimed is: 4. A compound in' accordance with claim 2 having 1. Acompound having the formula: the name 7-chloro-5,l l-

65 dihydrodibenz[b,e][ l,4]oxazepine-5-propionitrile. 5. A compound inaccordance with claim 2 having O0 on)", the name 5,1 l-dihydro-7-trifluromethyldibenz[b,e][ 1,4]oxazepine-5- butyronitrile.

22;; 3 UNITED STATES PATENT OFFICE"; I

l QERTIFICATE 0F CORRECTION Paten No. 3,744, 983 Dated June 26, 1973ITWeR -T Harrv Louis Yales 'R g esh Petiqara It is certified that errorappears in the above-identified patent and that said Letters Patent areherebyhcorrected as shown below:

.In the listing for lnventors, "Remesh Pet igara" should read -RameshPetigara-n Column 1, lines 10-15, the formula should read A-COOH Column1,' lines 45-50,, the formula should read H II Colurfin'l, lines 55-58/the formula should read CH :C1HC N III- Column 2, line 3, "CH :CHRON"should read CH2: CHRCN Column 2, line 16, "prepartlng' should're'ad--preparing-.

C olu'1 nn 3,l' line 45 "produee'" should read -product-.

Column 4,

line 16, "pripionitrile" should read --propionitrile--.

W050 m'rrn STATES PATENT OFFICE (5/69) v t QER'HFICATE OF CQRRECTIONiyatant ND '3 741,983 v Dated J h 1973 Inventor) Harry Louis Yale, Ramesh Petigara P 2 It is certified that error appears in theabove-identified patent and that said Letters Patent are herebycorrected as shown below:

column 4, line 47, "on,cx,oa -trifluoro2nitro-" should read-d,,on,o-trifluoro-2-nitro Column 6, line 1, "435- g.-" should read 453g. "Column 7, line 48, Followig" should read Following-.

,Column 7*, Example 8, should read as follows; 1 a ---'--7--Chloro-5,ll-dihydrodibenzo [b,e][l,4]thiazepine-5-(ob pentyl)--propionic-acid 1 Following the procedure.

Column 8, line 12', insert' a comma after in vacuo" Column 8, line 59,delete "is removed as it also appears I on the line .above it. J

Column l0, claim 3, the formula should be:

lower alkylene-CN Column 10, line 67, "trifluromethyldibenz" should readtrifluoromethyldibenz- Signed and sealed this 29th day of January 1974.y Y

Attest:

EDWARD MI.FLETCHER,JR. RENE D. TEGTMEYER Attesting Officer ActingCommissioner of Patents v

2. A compound having the formula:
 3. A compound of claim 1 having theformula:
 4. A compound in accordance with claim 2 having the name7-chloro-5,11-dihydrodibenz(b,e)(1,4)oxazepine-5-propionitrile.
 5. Acompound in accordance with claim 2 having the name5,11-dihydro-7-trifluromethyldibenz(b,e)(1,4)oxazepine-5-butyronitrile.